(2024) 22:306
Zhou et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03507-8

BMC Medicine

RESEARCH ARTICLE

Open Access

Short- and long-term impact of aspirin
cessation in older adults: a target trial emulation
Zhen Zhou1,2†, Katherine L. Webb1†, Mark R. Nelson2, Robyn L. Woods1, Michael E. Ernst3,4, Anne M. Murray5,6,Andrew T. Chan7,8, Andrew Tonkin1, Christopher M. Reid1,9, Suzanne G. Orchard1, Brenda Kirpach5, Raj C. Shah10,
Nigel Stocks11, Jonathan C. Broder1 and Rory Wolfe1*   

Abstract
Background The net benefit of aspirin cessation in older adults remains uncertain. This study aimed to use observational data to emulate a randomized trial of aspirin cessation versus continuation in older adults without cardiovascular disease (CVD).
Methods Post hoc analysis using a target trial emulation framework applied to the immediate post-trial period(2017–2021) of a study of low-dose aspirin initiation in adults aged ≥ 70 years (ASPREE; NCT01038583). Participantsfrom Australia and the USA were included if they were free of CVD at the start of the post-trial intervention period(time zero, T0) and had been taking open-label or randomized aspirin immediately before T0. The two groups
in the target trial were as follows: aspirin cessation (participants who were taking randomized aspirin immediately
before T0; assumed to have stopped at T0 as instructed) versus aspirin continuation (participants on open-label
aspirin at T0 regardless of their randomized treatment; assumed to have continued at T0). The outcomes after T0
were incident CVD, major adverse cardiovascular events (MACE), all-cause mortality, and major bleeding during 3, 6,
and 12 months (short-term) and 48 months (long-term) follow-up. Hazard ratios (HRs) comparing aspirin cessation
to continuation were estimated from propensity-score (PS) adjusted Cox proportional-hazards regression models.
Results We included 6103 CVD-free participants (cessation: 5427, continuation: 676). Over both short- and longterm follow-up, aspirin cessation versus continuation was not associated with elevated risk of CVD, MACE, and allcause mortality (HRs, at 3 and 48 months respectively, were 1.23 and 0.73 for CVD, 1.11 and 0.84 for MACE, and 0.23
and 0.79 for all-cause mortality, p > 0.05), but cessation had a reduced risk of incident major bleeding events (HRs at 3
and 48 months, 0.16 and 0.63, p < 0.05). Similar findings were seen for all outcomes at 6 and 12 months, except for alowered risk of all-cause mortality in the cessation group at 12 months.
Conclusions Our findings suggest that deprescribing prophylactic aspirin might be safe in healthy older adults
with no known CVD.
Keywords Aspirin, Target trial, Cardiovascular disease, Elderly, Cessation, Hemorrhage†

Zhen Zhou and Katherine L. Webb contributed equally as first author.

*Correspondence:Rory Wolfe
rory.wolfe@monash.edu
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Zhou et al. BMC Medicine(2024) 22:306

BackgroundThe net clinical benefit of daily low-dose aspirin initiation in older populations without clinical manifestationof cardiovascular disease (CVD) was unknown until
2018 when the ASPirin in Reducing Events in the Elderly(ASPREE) study was published [1–3]. The ASPREE trial
found that aspirin did not extend disability-free survival
or reduce CVD events but increased the risk of major
bleeding and cancer death. This evidence led to a recommendation in clinical guidelines against aspirin initiationin older adults for primary prevention of CVD [4–6].
Notwithstanding this, a recent US national population
survey of 50,000 + respondents showed that 46% of individuals aged ≥ 70 years who had no prior history of CVD
reported regular aspirin use in 2019, after the ASPREE
trial findings were published [7]. As 89% of participantsin the ASPREE trial reported no regular aspirin use
prior to enrollment, the main ASPREE results primarily
addressed whether aspirin should be initiated in older
adults and not whether aspirin should be ceased in those
who reach older ages while already taking aspirin [8].
Whether it is safe to cease aspirin remained a subject of
debate. A randomized trial of deprescribing aspirin (compared to continuation of aspirin use) would be optimal toprovide definitive evidence to answer this question. However, such a trial is unlikely to be conducted, and we recognized that ASPREE participants as they transitioned
from the trial to post-trial observational follow-up could
be informative.
At the conclusion of the ASPREE trial and after amedian of 4.7 years of follow-up, approximately 63% ofparticipants were still taking randomized study medication (62% in the aspirin arm and 64% in the placeboarm) [1–3]. All participants received a notification letter
directing them to immediately cease study medication.
The letter also advised that any participants taking openlabel aspirin by recommendation of their doctor should
continue to take their aspirin. This provided a unique
opportunity to utilize observational data from the period
immediately following the intervention phase of ASPREE
to emulate an aspirin deprescribing trial. In this context,
we designed an analysis of ASPREE’s post-intervention
period to examine whether aspirin cessation, compared
to continuation, impacted short- and long-term risk of
CVD, all-cause mortality, and major bleeding in participants who had not experienced any CVD-related clinicalevent and hence had no indication for aspirin use.
Methods
Data source

We used the post-trial intervention data of ASPREE forthis target trial emulation. ASPREE was a large-scale randomized trial (NCT01038583) of low dose aspirin versus

Page 2 of 11

placebo among 19,114 adults aged over 70 years (≥ 65
years for US minorities), who were free of cardiovascular events, dementia, and major physical disability at trial
enrolment. The recruitment was undertaken between
2010 and 2014, and the participants were followed up
for a median of 4.7 years. The intervention phase of the
ASPREE trial ended on 12 June 2017 when the notification letter was sent to all participants. Study visits continued to January 2018 without intervention. From 13 June
2017, participants provided consent to ASPREE-eXTension (ASPREE-XT), an extended observational period [9].
The occurrence of health events after 12 June 2017 continued to be followed up with the same rigor as during
the trial intervention phase. After the trial intervention
phase, participants remained blinded to their study medication assignment and unaware of the principal findingsof the trial for a further 15 months. An unblinding letter
was sent to all participants on 14 September 2018 whenthe main findings of the ASPREE trial were published.
The timeline of the ASPREE trial intervention phase andpost-intervention phase for our analysis is presented inFig. 1.
Study design

We adopted a target trial framework to guide our analysis using observational data from ASPREE-XT that wouldemulate a randomized trial comparing aspirin cessation
to continuation [10–12]. The emulation involved two
main steps. The first step was to clearly define the causal
question within a hypothetical randomized trial protocol,
which included the defining of eligibility criteria, treatment strategies, treatment assignment, start (time zero,henceforth referred to as “T0”) and end of follow-up, outcomes, causal contrasts, and planned statistical analysis.
The second step was to emulate these trial protocol components using the observational data. Additional file 1:
Table S1 outlines the detailed specifications of the target
trial emulated for this study.
Eligibility criteria

The original selection criteria of the ASPREE trial applied[1–3]. Additionally, only surviving individuals at T0
were included in the target trial and only if at T0 they
had remained free of any adjudicated cardiovascular
event and did not have a reported likely cardiovascular
event or use of medication for likely secondary prevention purpose. In other words, an exclusion criterion was
any possible clinical indication for aspirin. Adjudicatedcardiovascular events included non-fatal myocardial
infarction (MI), coronary heart disease death, stroke,and hospitalization for heart failure (HF), all of whichwere adjudicated by an expert clinical panel. Cardiovascular events self-reported or recorded in medical reports

Zhou et al. BMC Medicine(2024) 22:306

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Fig. 1 The overall design and main results of this study. A, B The ASPREE trial intervention phase ended on 12 June 2017, on which day
the notification letter was sent to participants to inform the cessation of randomized study medication. Thus, 13 June 2017 serves as the index
date (time zero, T0) of this analysis. Excluded from this analysis were ASPREE participants who (1) had no continued follow-up after T0 (n = 2319;
primary reason was death during the trial) or (2) had adjudicated CVD events (n = 612) or reported other possible indications to aspirin use(n = 2398; for example, angina or mini stroke) prior to T0 or (3) had never started aspirin (randomized to placebo and report of no open-label
aspirin use before T0), which left 6103 participants with whom to emulate a target trial. Among these included participants, those who wereoriginally randomized to aspirin and compliant with the study medication until T0 (stop) with no report of open-label aspirin use recently prior
to T0 constitute the cessation group (n = 5427), and participants who were randomized to either aspirin or placebo and reported recent open-label
regular aspirin use prior to T0 constitute the continuation group (n = 676). From T0, participants entered an observational phase during whichclinical data were collected from participants via scheduled annual in-person visits and 6-monthly phone calls. At the fourth annual XT visit, there
remained 47% of participants in the aspirin continuation group reporting the use of open-label aspirin and 87% in the cessation group reporting
no aspirin use. C The main results showed no increased cardiovascular disease (CVD), major adverse cardiovascular events (MACE), or mortality risks
and a lower risk of major bleeding with aspirin cessation. A CVD event was defined as adjudicated non-fatal myocardial infarction, cardiovasculardeath, stroke, and hospitalization for heart failure. MACE was defined as adjudicated ischemic stroke, myocardial infarction, and coronary heartdisease death

included events sent to the MI, HF, or stroke adjudication committee but rejected as not meeting the outcome
criteria, and angina, heart/chest pain, transient ischemic
attack, atrial fibrillation, deep vein thrombosis/pulmonary embolism, or any cardiac/vascular hospitalizationand self-report of medications commonly used for secondary prevention included nitrates, ranolazine, or platelet aggregation inhibitors excluding aspirin.
Start and end of follow‑up

T0 (13 June 2017) was defined as the day following the dispatch of the letter notifying the end of trial

intervention. All participants were followed up until
the incidence of outcome events, death, or their fourth
ASPREE-XT annual visit (between 2021 and 2022),
whichever occurred first (Fig. 1). During both ASPREE
and ASPREE-XT periods, clinical data were collectedfrom participants via scheduled annual in-person visits
and 6-monthly phone calls. For those who were unable tobe contacted, their medical records were reviewed. Dataof aspirin use and other concomitant medications weregathered either from primary care physician records by
research staff or through self-reports of current medication use during annual visits. Compliance to randomized

Zhou et al. BMC Medicine(2024) 22:306

aspirin was determined by count of used pills > 0 fromreturned study medication bottles, and compliance toopen-label aspirin was based on self-reported use at eachannual visit.
Treatment strategies and assignments

We compared participants who continued taking aspirin versus those who discontinued it. The continuationgroup consisted of participants who reported recent
open-label aspirin use at their most recent annual visit
before T0 (average 184 days prior to T0), regardless of
their ASPREE randomized assignment. We assumed
that participants in the continuation group were still taking aspirin at T0 and continued doing so thereafter. The
cessation group consisted of participants from the randomized aspirin arm, who, based on a count of returned
study pills, were determined to have taken randomized
aspirin in the last calendar year of trial intervention (year2017) and did not report recent open-label aspirin use
before T0. We assumed that participants in the cessationgroup were still taking randomized aspirin at the time ofreceiving the notification letter and immediately ceased
use as instructed. These assumptions of adherence to thecourse of action instructed in the letter emulate an intention-to-treat analysis approach in a randomized trial [11].
Treatment randomization was emulated through a propensity score (PS)-based method, as detailed in the “Statistical analysis” section.
Outcomes

Study outcomes were incident CVD (non-fatal MI, cardiovascular death, stroke, and hospitalization for HF),
major adverse cardiovascular events (MACE), all-cause
mortality, and major bleeding events. MACE included
fatal and non-fatal ischemic stroke, non-fatal MI, andcoronary heart disease death. Major bleeding events
included clinically significant bleeding, hemorrhagic
stroke, and subarachnoid hemorrhage. Clinically significant bleeding was defined as bleeding that led to transfusion, hospitalization, prolongation of hospitalization,
surgery, or death. For analysis of major bleeding, participants who had major bleeding events before T0 were
further excluded. All clinical events in these outcomes
were adjudicated by panels of clinical experts who weremasked to treatment randomization and follow-up status
with respect to aspirin use [1–3].
Causal contrast

Using an intention-to-treat approach, this study compared aspirin cessation versus continuation at T0, regardless of subsequent treatment crossovers during thefollow-up period.

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Statistical analysis

To emulate random treatment assignment, we created apropensity score (PS) of aspirin cessation for each participant using logistic regression, with the following
covariates: age, gender, race/ethnicity/country (white
Australian, white US, Hispanic, black, other), systolic anddiastolic blood pressure, total cholesterol (TC), triglycerides, estimated glomerular filtration rate (eGFR using
CKD-EPI equation [13]), smoking (current/former vs.
never), diabetes, education (< 12 vs. ≥ 12 years), use ofstatins, anti-hypertensives, non-steroidal anti-inflammatory drugs (NSAIDs), and antithrombotic agents (excluding aspirin), and family history of MI. Covariate values
came from annual visits that occurred within 2 years
prior to T0; if unavailable from these visits, values were
imputed using a linear model (< 0.5% of covariate values). Conceptually, the PS was equivalent to one minus
the propensity of being on open-label aspirin for primaryprevention at T0. Differences in covariates between thetwo groups before and after applying the PS approachwere checked by using an absolute standardized difference (ASD) measure, where a difference ≥ 0.1 indicatesimbalance.
For outcome analysis, Cox proportional-hazards
regression models were used to generate hazard ratios(HRs) and 95% confidence intervals (CIs) of each outcome at 3, 6, and 12 months and over the full time periodof follow-up (approximately 4 years) after T0, withadjustment made for the PS [14]. The proportional hazards assumption was assessed with Schoenfeld residuals,
and no violations were found.
Three sensitivity analyses were performed with different eligibility criteria: (1) inclusion of participants who
had a possible aspirin indication, to assess the impact ofaspirin cessation in all participants without confirmed
usage for secondary prevention (2) excluding participants
who reported the use of other antithrombotic medications for primary prevention which might increase therisk of bleeding associated with aspirin; and (3) including
more covariates in the propensity score that are associated with CVD and death risk in older people, including
high-density-lipoprotein cholesterol (HDL-c), fasting
plasma glucose, alcohol consumption, body mass index(BMI), grip strength, and gait speed.
We additionally performed a per-protocol analysis using an inverse-probability-of-censoring weights(IPCW) approach [15]. Endpoint-specific analyses wereconducted in which participants remaining alive in primary prevention were right-censored at the first occurrence of continuation/cessation nonadherence. We
applied IPCW to upweight remaining participants for
imparted informative censoring at selected time points.
Non-adherence was defined in the cessation group asZhou et al. BMC Medicine(2024) 22:306

the initiation of open-label aspirin; in the continuationgroup, it was the cessation of open-label aspirin. Weights
were calculated separately for the two treatment groups
using the same set of covariates used for the propensity
score and additionally time-varying covariates for CVD
events (in mortality and major hemorrhage analyses) andmajor hemorrhage events (in CVD, MACE, and mortality
analyses). The product of time-varying IPCW and timefixed PS weights were used in weighted Cox proportional
hazards models [16].
All statistical tests were 2-sided, and p < 0.05 was considered statistically significant. Analyses were conductedusing R version 4.0.2 (R Core Team, 2020).
Role of the funding source

The funding sources and drug provider played no role inthe design, conduct, and reporting of the ASPREE trial,
ASPREE-XT, and this analysis.

Results
Study population and baseline characteristics

A flow chart of participant selection is presented in Fig. 1
and Additional file 1: Fig. S1. After excluding 2319 participants with no follow-up beyond T0, 3010 with an adjudicated cardiovascular event and/or other possible aspirin
indications, and 7682 who did not take aspirin or lacked
relevant information to confirm their aspirin use before
T0, we included 6103 participants for the final analysis,
with 676 (11.0%) categorized into the aspirin continuation group and 5427 (89.0%) into the cessation group.
Adherence to aspirin use at > 1 year was 72.5% in the continuation group, and adherence to aspirin non-use was
91.6% in the cessation group at this time point. Adherence rates remained high at approximately 4.5 years after
T0 (Fig. 1). Only 47 (8 [1.2%] continuation, 39 [0.7%] cessation) participants withdrew during follow-up, with amean (SD) follow-up time of 1.9 (1.2) years.
Compared with the aspirin continuation group, participants in the aspirin cessation group were, on average, slightly younger and more likely to be Australian andhad higher total cholesterol and eGFR levels. The cessation group also had a lower prevalence of self-reported
diabetes and family history of MI and was less likely touse statins, anti-hypertensive agents, and antithrombotic
medications. Participants in the continuation group hada higher prevalence of self-reported aspirin use prior to
ASPREE, although this variable was not adjusted for in
the PS model. After applying PS, all covariates were wellbalanced (ASDs < 0.1) (Table 1).
Short‑term follow‑up (3–12 months)

The observed incidence rates of CVD and MACE outcomes were comparable between the cessation andPage 5 of 11

continuation groups at 3 and 6 months and were numerically lower in the cessation group at 12 months, while theobserved incidence rates of all-cause mortality and major
bleeding events were numerically lower in the cessationgroup than the continuation group throughout the follow-up period (Table 2). The PS-adjusted models foundno statistically significant association between aspirin
cessation and incident CVD events at 3, 6, and 12 months(PS-adjusted HRs [95% CI]: 1.23 [0.27–5.58] at 3 months,
1.49 [0.44–5.03] at 6 months, and 0.69 [0.33–1.44] at 12
months, all p values ≥ 0.30); also, there was no significant association between aspirin cessation and MACE
(PS-adjusted HRs [95% CI]: 1.11 [0.24–5.13] at 3 months,
1.39 [0.41–4.73] at 6 months, and 0.73 [0.34–1.58] at 12
months, all p values ≥ 0.40). Aspirin cessation was associated with a significantly lower risk of all-cause mortality
at 12 months (PS-adjusted HR [95% CI]: 0.39 [0.20–0.77])
but not at 3 and 6 months (0.23 [0.04–1.32] at 3 months
and 0.76 [0.15–3.75] at 6 months). For bleeding, cessation of aspirin was associated with an 84% (PS-adjusted
HR [95% CI]: 0.16 [0.03–0.77]), 63% (0.37 [0.09–1.47]),
and 63% (0.37 [0.14–0.96]) reduced risk of incident major
bleeding events at 3, 6, and 12 months respectively (Fig. 1,
Table 2), with the association being statistically significant at 3 and 12 months. Cumulative incidence curves ofmajor bleeding events for the two groups diverged fromT0, indicating that bleeding risk lowered soon after discontinuing aspirin (Fig. 2).
Long‑term follow‑up (48 months)

Compared to the aspirin continuation group, the cessation group had a lower incidence rate of CVD and
MACE over long-term follow-up (CVD: 12.9 versus 18.2
events per 1000 person-years; MACE: 10.2 versus 12.2
events per 1000 person-years). No significant association with aspirin cessation was found for CVD, MACE,
and all-cause mortality (CVD, PS-adjusted HR [95% CI]:
0.73 [0.53–1.01], p = 0.06; MACE: PS-adjusted HR [95%CI]: 0.84 [0.57–1.24], p = 0.38; all-cause mortality, PSadjusted HR [95% CI]: 0.79 [0.61–1.03], p = 0.08). For
major bleeding, there was a similar finding during theextended follow-up as the short-term follow-up periodwith a 37% reduced risk of bleeding with aspirin cessation(PS-adjusted HR [95% CI]: 0.63 [0.41–0.98], p = 0.04).
(Table 2, Fig. 1 and Fig. 2).
Congruent with the intention-to-treat analysis, theper-protocol analysis found no significant associations ofaspirin cessation with CVD, MACE, and all-cause mortality at 48 months and a significant association between
aspirin cessation and a reduced risk of major bleeding (IPCW- and PS-adjusted HR [95% CI]: 0.48 [0.29,
0.79]) at 48 months (Table 3). Results from other sensitivity analyses with altered eligibility criteria were also

Zhou et al. BMC Medicine(2024) 22:306

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Table 1 Participant characteristics at time zero (13 June 2017)
Overall (n = 6103)

Aspirin continuation (n = 676)

Aspirin cessation (n = 5427)

Absolute
standardized
difference(ASD)
BeforeAfter

Age, years (min–max)

79.2 ± 4.4 (67.9–100.2)

80.0 ± 4.8 (68.0–97.1)

79.1 ± 4.3 (67.9–100.2)

0.21

0.05

Male gender2661 (43.6)

292 (43.2)

2369 (43.7)< 0.01< 0.01White Australian5293 (86.7)

504 (74.6)

4789 (88.2)

0.14< 0.01White US339 (5.6)

72 (10.7)267 (4.9)

0.06< 0.01

Hispanic

253 (4.1)

59 (8.7)

194 (3.6)

0.05< 0.01Black

135 (2.2)

28 (4.1)

107 (2.0)

0.02< 0.01

Other

83 (1.4)

13 (1.9)70 (1.3)< 0.01< 0.01

Education ≥ 12 years

3448 (56.5)

414 (61.2)

3034 (55.9)

0.05< 0.01

Total cholesterol, mg/DL

197.2 ± 38.8

188.3 ± 41.6

198.3 ± 38.3

0.26

0.02

Triglycerides, mg/DL

118.5 ± 56.6

117.7 ± 53.6

118.6 ± 56.9

0.02

0.03

SBP, mmHg

136.9 ± 16.9

137.1 ± 17.3

136.9 ± 16.8

0.01

0.01

DBP, mmHg

74.2 ± 9.7

74.0 ± 9.8

74.2 ± 9.7

0.02

0.01

Smoking, ever

2621 (42.9)

302 (44.7)

2319 (42.7)

0.02< 0.01eGFR, ml/min/1.73 m­ 2

69.9 ± 14.4

68.8 ± 15.4

70.0 ± 14.2

0.09

< 0.01

Self-report diabetes

600 (9.8)

98 (14.5)502 (9.3)

0.05< 0.01

Statin use

2206 (36.1)

341 (50.4)

1865 (34.4)

0.16

0.02

Anti-hypertensive agents use

3630 (59.5)

475 (70.3)3155 (58.1)

0.12

0.02

NSAID use

901 (14.8)

117 (17.3)

784 (14.4)

0.03< 0.01Anti-thrombotic use (excluding aspirin)

466 (7.6)

92 (13.6)

374 (6.9)

0.07< 0.01

Family history of MI

2571 (42.1)

320 (47.3)

2251 (41.5)

0.06< 0.01Pre-trial aspirin use (not adjusted)

675 (11.1)

134 (19.8)

541 (10.0)––

Race/ethnicity/country

Abbreviations: SBP systolic blood pressure, DBP diastolic blood pressure, eGFR estimated glomerular filtration rate, MI myocardial infarction, NSAIDs non-steroidal antiinflammatory drugs
Continuous variables are presented as mean ± SD and categorical variables are presented as n (%)

generally congruent with the main short-term and longterm findings, except for the non-significant (p = 0.06)
reduction of major bleeding at 48 months in the analysis
including more covariates in the PS model (Additional
file 1: Tables S2-S5).

Discussion
Compared with aspirin continuation, there was no evidence of an increase in the rates of incident CVD or
MACE events or all-cause mortality over both short-term(3–12 months) and long-term follow-up (48 months)
periods among participants who ceased aspirin at theend of the trial. However, aspirin cessation was associated with a significantly reduced risk of major bleedingby between 63 and 84% when compared to aspirin continuation during the 3- to 12-month timeframe and by
37% during the extended follow-up. Our findings support
the safety of stopping aspirin in those aged ≥ 70 years
where it is being used in the context of primary CVD
prevention.

The safety of discontinuing daily preventive aspirin has
been a great concern due to a proposed risk of unmasking of subclinical CVD and prothrombotic reboundeffects that could prompt a CVD event [17, 18]. Aspirin
discontinuation leads to an inevitable progressive recovery of cyclooxygenase-1 (COX-1) activity that promotes
the production of prostaglandin, which is converted tothromboxane-A2 ­(TXA2) by thromboxane synthase in
fresh platelets [19]. ­TXA2 promotes platelet activation
and aggregation on the surface of the damaged vessel
walls leading to a thrombotic occlusion and subsequently
an acute thrombotic event [20, 21]. It has been estimatedthat acute coronary artery and cerebrovascular events
could be triggered within 7 days to 4 weeks following
aspirin cessation [19–22]. However, in this study, we
found no noticeable increase in risks of CVD and MACE
with aspirin cessation at 3-month follow-up. In addition,
there was no significant association between aspirin cessation, CVD, and MACE over a longer follow-up (6, 12,
and 48 months). These insights support the hypothesis

Zhou et al. BMC Medicine(2024) 22:306

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Fig. 2 Cumulative incidence plots for CVD (A), MACE (B), major bleeding (C), and all-cause mortality (D) in the aspirin continuation and cessationgroups. The red line represents the continuation group (Cont), and the blue line represents the cessation group (Cess). The shading denotes 95%
confidence intervals. Abbreviations: CVD, cardiovascular disease; MACE, major adverse cardiovascular eventthat ceasing aspirin reduces clinically significant bleeding with no rebound effect linked to increased CVD risk.
In line with our findings, a randomized trial comparing
the short-term effect of continued aspirin versus placeboin 4382 patients undergoing noncardiac surgery who had
been taking aspirin for vascular conditions before trial
entry found no evidence of an immediate aspirin withdrawal effect [23]. In that study, aspirin continuation was
not associated with the risk of a composite outcome ofdeath or non-fatal myocardial infarction (HR [95% CI]:
1.00 [0.81–1.24]) at 30 days, but an increased risk of thecomposite outcome of life-threatening and major bleeding was observed although this finding was not statistically significant (HR [95% CI]: 1.20 [0.94–1.55]).
The significant decrease in major bleeding risk withaspirin cessation throughout the entire follow-up period
and a decreased risk in all-cause mortality with aspirin
cessation at 12 months in our analysis supports clinicalguidelines that recommend against aspirin use in thisage group for primary prevention due to its significantly
increased risk of major bleeding events and lack of overall benefit [4–6]. The weakened association between aspirin continuation and bleeding risk at 4-year follow-up
may be explained by the participants on open-label aspirin being made aware of the ASPREE trial results at 15
months after T0 and opting to stop open-label aspirin use
at that time. When analyses were adjusted for treatment

adherence, the evidence of elevated bleeding risk in thecontinuation group was even more compelling. The
cumulative incidence plot suggests that the bleeding risk
between the aspirin cessation and continuation groups
differentiated soon after the commencement of followup. These findings agree with our previous analysis of
the ASPREE participants when they entered the trial,
approximately 4–5 years earlier [24]. In that post hoc
analysis, we restricted to individuals reporting aspirin
use prior to randomization (≥ 2 days/week) and investigated the effect of aspirin cessation (randomized placebo)
versus continuation (randomized aspirin) at the start oftrial. Discontinuing aspirin (through randomization toplacebo) had no impact on CVD, MACE, all-cause mortality, and major bleeding events compared with continued aspirin use over a median of 4.7-year follow-up [24].
The robustness of that analysis was limited by the small
sample size (n = 1714) and a 4-week placebo run-in phasefor the trial that prevented capture of the short-term
unmasking effect, although the findings were echoed inmeta-analysis with another similar trial [25]. The present
study reported here reinforces our conclusions from theprevious analysis, and together the findings reassure thebenefits of aspirin cessation (reducing bleeding risk) inolder adults in the context of primary CVD prevention,
an aspect which has often been less emphasized compared with its potential in increasing CVD risk. More

Zhou et al. BMC Medicine(2024) 22:306

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Table 2 The hazard of each study outcome in the aspirin cessation group versus the continuation group during four follow-up periods
EventsIncidence rate (per 1000 py)

Unadjusted HR (95% CI)pPS-adjusted HR (95% CI)

p  Continuation

2

11.85

Ref

1.00

Ref

0.79

  Cessation

16

11.81

1.00 (0.23, 4.34)  Continuation

3

8.90

Ref

  Cessation

30

11.09

1.25 (0.38, 4.08)  Continuation

9

13.39

Ref

  Cessation

49

9.07

0.68 (0.33, 1.38)  Continuation

46

18.20

Ref

  Cessation

281

12.94

0.71 (0.52, 0.96)  Continuation

2

11.85

Ref

  Cessation

14

10.33

0.87 (0.20, 3.84)  Continuation

3

8.90

Ref

  Cessation

27

9.98

1.12 (0.34, 3.70)  Continuation

8

11.90

Ref

  Cessation

45

8.33

0.70 (0.33, 1.48)

31

12.22

Ref

221

10.16

0.83 (0.57, 1.21)  Continuation

3

18.35

Ref

  Cessation

4

2.98

0.16 (0.04, 0.73)  Continuation

3

9.18

Ref

  Cessation

8

2.98

0.32 (0.09, 1.22)  Continuation

6

9.20

Ref

  Cessation

17

3.17

0.34 (0.14, 0.87)  Continuation

26

10.59

Ref

  Cessation

136

6.27

0.58 (0.38,0.89)

CVD (n = 6103)
3 months

1.23 (0.27, 5.58)

6 months
0.72

Ref

0.52

1.49 (0.44, 5.03)

12 months
0.28

Ref

0.32

0.69 (0.33, 1.44)

48 months
0.03

Ref

0.06

0.73 (0.53, 1.01)

MACE (n = 6103)
3 months

0.86

Ref

0.89

1.11 (0.24, 5.13)

6 months
0.85

Ref

0.60

1.39 (0.41, 4.73)

12 months
0.35

Ref

0.42

0.73 (0.34, 1.58)

48 months  Continuation
Cessation

0.33

Ref

0.38

0.84 (0.57, 1.24)

Major bleedinga (n= 6028)
3 months
0.02

Ref

0.02

0.16 (0.03, 0.77)

6 months
0.10

Ref

0.16

0.37 (0.09, 1.47)

12 months
0.02

Ref

0.04

0.37 (0.14, 0.96)

48 months
0.01

Ref

0.04

0.63 (0.41, 0.98)

All-cause mortality (n = 6103)
3 months  Continuation

2

11.85

Ref

  Cessation

4

2.95

0.25 (0.05, 1.36)  Continuation

2

5.93

Ref

  Cessation

9

3.32

0.56 (0.12, 2.59)  Continuation

12

17.88

Ref

  Cessation

35

6.47

0.36 (0.19, 0.70)  Continuation

69

25.06

Ref

  Cessation

395

17.18

0.68 (0.53, 0.88)

0.11

Ref

0.10

0.23 (0.04, 1.32)

6 months
0.46

Ref

0.73

0.76 (0.15, 3.75)

12 months< 0.01Ref

0.01

0.39 (0.20, 0.77)

48 months< 0.01

Ref
0.79 (0.61, 1.03)

Abbreviations: CVD cardiovascular disease, MACE major adverse cardiovascular events, PS propensity score, HR hazard ratio, CI confidence intervalaA total of 75 participants who experienced major bleeding prior to 13 June 2017 were removed from the major bleeding analysis

0.08

Zhou et al. BMC Medicine(2024) 22:306

Page 9 of 11

Table 3 Comparison of intention-to-treat (PS-adjusted) and per-protocol (IPCW- and PS-adjusted) hazard ratios of each study
outcome in the aspirin cessation versus continuation group during long-term follow-up to 48 months
PS-adjusted HR (95% CI)

p  Continuation

Ref

0.06

  Cessation

0.73 (0.53, 1.01)

IPCW- and PS-adjusted HR (95%
CI)

p

Ref

0.30

CVD (n = 6103)
48 months

0.80 (0.53, 1.22)

MACE (n = 6103)
48 months  Continuation

Ref  Cessation

0.84 (0.57, 1.24)

0.38

Ref

0.65

0.89 (0.55, 1.46)

Major bleedinga (n = 6028)
48 months  Continuation

Ref  Cessation

0.63 (0.41, 0.98)

0.04

Ref

0.004

0.48 (0.29, 0.79)

All-cause mortality (n= 6103)
48 months  Continuation

Ref  Cessation

0.79 (0.61, 1.03)

0.08

Ref

0.14

0.77 (0.54, 1.09)

Abbreviations: CVD cardiovascular disease, MACE major adverse cardiovascular events, PS propensity score, IPCW inverse probability of censoring weight, HR hazard
ratio, CI confidence intervalaA total of 75 participants who experienced major bleeding prior to 13 June 2017 were removed from the major bleeding analysis

studies with high-quality data and larger sample sizes are
warranted to confirm our results [26].
This study has limitations. First, we assumed that all
participants on randomized aspirin before T0 would
immediately stop taking the study medication after
receiving the letter, and those who reported open-label
aspirin use in the most recent follow-up visit before T0
would continue aspirin thereafter. These assumptions
could lead to misclassification bias, likely towards null
effects; however, the data we presented on aspirin use
during follow-up indicated that the assumptions werereasonable. Furthermore, a per-protocol analysis was
performed so as not to underestimate safety concernsof deprescribing aspirin; results from these were consistent with our main findings for the long-term effects,
further indicating that our assumptions were reasonable.
Second, the event numbers in the relatively short timeframe of follow-up were small for all outcomes, leading
to wide CIs for the 3-, 6-, and 12-month effect estimates.
The data presented do not out rule the possibility of an
adverse effect of aspirin cessation on CVD at 6 months.
Third, our findings were based on a sample constituting
predominantly white healthy older adults and may not be
generalizable to other race/ethnicity groups or populations in different settings. Last, the aspirin continuationgroup seemed to have a higher CVD risk at T0, despite
the exclusion of participants with possible and probable
CVD events or using of medication for likely secondary

prevention purpose. Although the propensity-scoreapproach was employed to account for the higher CVD
risk and minimize potential confounding, the presence ofresidual bias in comparing aspirin cessation with continuation cannot be ruled out.
Notwithstanding these limitations, this analysis has
some key strengths including using a robust approach toemulate a randomized trial via the PS technique, the useof well-characterized, highly complete data of older individuals with rigorous long-term follow-up, adjudicationof all study endpoints, and the ability to identify all participants with a possible aspirin indication at time zero.

Conclusions
This analysis of observational data to emulate a deprescribing trial found no short-term or long-term harmful impact of aspirin cessation on the risk of CVD andall-cause mortality and a reduced risk of major bleeding
events. These findings suggest that deprescribing aspirin
might be safe in healthy individuals with no known CVD
who are aged 70 years or above.
Abbreviations
ASD	Absolute standardized difference
ASPREE	Aspirin in Reducing Events in the Elderly
ASPREE-XT	ASPREE-eXTension
BMI	Body mass index
CI	Confidence interval
CKD-EPI	Chronic Kidney Disease Epidemiology Collaboration
COX-1	Cyclooxygenase-1

Zhou et al. BMC Medicine(2024) 22:306

CVD	Cardiovascular disease
eGFR	Estimated glomerular filtration rate
HDL-C	High-density lipoprotein cholesterol
HF	Heart failureHR	Hazard ratio
IPCW	Inverse probability of censoring weighting
MACE	Major adverse cardiovascular events
MI	Myocardial infarction
NSAID	Non-steroidal anti-inflammatory drug
PS	Propensity score
TC	Total cholesterol
TXA2	Thromboxane-A2

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03507-8.
Additional file 1: Fig. S1. Participant selection flowchart. Table S1. Target
trial framework. Table S2. Outcome analysis additionally including
participants with possible aspirin indications. Table S3. Outcome analysis
additionally excluding participants with antithrombotic use. Table S4. Participant characteristics at T0 with additional variables included. Table S5.
Outcome analysis including additional covariates.
Acknowledgements
The authors would like to thank the ASPREE and ASPREE-XT participants who
gave their precious time to participate in ASPREE and ASPREE-XT, registeredgeneral practitioners, endorsing organizations, and all members of the ASPREE
and XT team.
Authors’ contributions
ZZ, KLW, MRN, RLW, MEE, AMM, ATC, AT, CMR, SGO, BK, RCS, NS, JCB, and
RW contributed to the concept and design of the study. KLW undertook all
statistical analyses. ZZ, KLW, and RW had full access to all of the data in the
study and take responsibility for the integrity of the data and the accuracy ofthe data analysis. ZZ, KLW, MRN, RW, RLW, MEE, AMM, and ATC had substantial
roles in the acquisition, analysis, or interpretation of data. ZZ and KLW drafted
the manuscript. MRN, RLW, MEE, AMM, ATC, AT, CMR, SGO, BK, RCS, NS, JCB,
and RW provided critical revision of the manuscript for important intellectual
content. All authors read and approved the final manuscript. RW provided
supervision.
Authors’ Twitter handles
Twitter handles: @aspree_org@zhenzhou11 (Zhen Zhou).
Funding
The ASPREE and ASPREE-XT studies are supported by grants (U01AG029824
and U19AG062682) from the National Institute on Aging and the National
Cancer Institute at the National Institutes of Health in the United States, by
grants (334047 and 1127060) from the National Health and Medical ResearchCouncil of Australia, and by Monash University and the Victorian Cancer
Agency.
Availability of data and materials
Requests for data access will be via the ASPREE principal investigators withdetails for applications provided through https://​aspree.​org/​aus/​for-​resea​rchers/ or https://​aspree.​org/​usa/​for-​resea​rchers/. The DOI of ASPREE is: https://​doi.​org/​10.​26180/​21715​979.​v2.

Declarations
Ethics approval and consent to participate
This post hoc analysis is exempt from ethics review because it uses existingdata from ASPREE and ASPREE-XT, and no additional information was collected from participants. The ASPREE and ASPREE-XT studies were approved
by local institutional review boards at each participating site, and all participants provided written informed consent for their participation. ASPREE-XTPage 10 of 11

ethics approval in Australia is with Alfred Health Human Research Ethics
Committee: HREC/17/Alfred/198 (Local Reference: Project 593/17). While inAustralia, one consent covered the entirety of ASPREE-XT, in the USA, due
to the transition to a single institutional review board (IRB) required for NIH
multi-site research (NOT-OD-16–094) implemented in May 2017, two separate
consent steps were employed—an initial 1-year consent for the XT01 visit
which was approved under each individual sites’ IRB during the first year oftransition from ASPREE to ASPREE-XT and a new consent for the subsequent
5 additional years of ASPREE-XT annual visits (XT02-XT06) approved under the
single IRB of record (The University of Iowa).
Consent for publication
Not applicable.
Competing interests
ZZ reported being funded through a National Heart Foundation Post-Doctoral
Fellowship. MN reported receiving honoraria from Sanofi and Amgen as
well as Bayer for materials in ASPREE and NHMRC grant support for STAREE.
AT reported receiving research support or honoraria from Merck, Pfizer,
and Amgen as well as Bayer for materials in the ASPREE trial and National
Health and Medical Research Council (NHMRC) grant support for the Statins
in Reducing Events in the Elderly (STAREE) trial. CR reported being fundedthrough a National Health and Medical Research Council Principal Research
Fellowship. RS serves as a non-compensated member of the Board of Directors of the Alzheimer’s Association –Illinois Chapter. RS’s institution, Rush
University Medical Center, receives research support for his role as a site
principal investigator or site sub-investigator for industry-initiated clinical trials
and research studies of Alzheimer’s disease sponsored by Amylyx Pharmaceuticals, Inc, Eli Lilly & Co., Inc., Genentech, Inc., Lundbeck, Inc., Merck & Co., Inc.,
Navidea Biopharmaceuticals, Novartis Pharmaceuticals, Inc., Roche Holdings
AG; and, Takeda Development Center Americas, Inc. He is also a member of
the Steering Committee of the PREVENTABLE clinical trial. AC reports receiving
research support or honoraria from Boehringer Ingelheim, Bayer Pharma AG,
Pfizer Inc., Freenome, Zoe Ltd. for work unrelated to this manuscript. Others
declare that they have no competing interests.
Author details
1
School of Public Health and Preventive Medicine, Monash University,
Melbourne, VIC, Australia. 2 Menzies Institute for Medical Research, Universityof Tasmania, Hobart, TAS, Australia. 3 Department of Pharmacy Practice and Science, College of Pharmacy, The University of Iowa, Iowa, IA, USA. 4 Department
of Family Medicine, Carver College of Medicine, The University of Iowa, Iowa,
IA, USA. 5 Division of Geriatrics, Department of Medicine Hennepin HealthCare,
Berman Centre for Outcomes and Clinical Research, Hennepin Healthcare
Research Institute, Minneapolis, MN, USA. 6 University of Minnesota, Minneapolis, MN, USA. 7 Clinical and Translational Epidemiology Unit, Massachusetts
General Hospital, Boston, MA, USA. 8 Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. 9 School of Population Health, Curtin
University, Perth, WA, Australia. 10 Department of Family & Preventive Medicine
and the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA. 11 Discipline of General Practice, University of Adelaide, Adelaide,
SA, Australia.
Received: 11 January 2024 Accepted: 1 July 2024

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